Isoprenoid compounds (also known as terpenoid compounds) comprise the most numerous and structurally diverse family of natural products. In this family, terpenoids isolated from plants and other natural sources are used as commercial flavor and fragrance compounds as well as antimalarial and anticancer drugs. A majority of the terpenoid compounds in use today are natural products or their derivatives. One example of isoprenoid compounds are carotenoids, which are a structurally diverse class of pigments derived from isoprenoid pathway intermediate products.
The source organisms (e.g., trees, marine invertebrates) of many of these natural products are neither amenable to the large-scale cultivation necessary to produce commercially viable quantities nor to genetic manipulation for increased production or derivatization of these compounds. Therefore, the natural products must be produced semi-synthetically from analogs or synthetically using conventional chemical syntheses. Furthermore, many natural products have complex structures, and, as a result, are currently uneconomical or impossible to synthesize. Such natural products must be either extracted from their native sources, such as trees, sponges, corals and marine microbes; or produced synthetically or semi-synthetically from more abundant precursors. Extraction of a natural-product from a native source is limited by the availability of the native source; and synthetic or semi-synthetic production of natural products can suffer from low yield and/or high cost. Such production problems and limited availability of the natural source can restrict the commercial and clinical development of such products.
The biosynthesis of isoprenoid natural products in engineered microbes could tap the unrealized commercial and therapeutic potential of these natural resources and yield less expensive and more widely available fine chemicals and pharmaceuticals. A major obstacle to high level terpenoid biosynthesis is the production of terpene precursors. Previous studies have shown that, when expressed in E. coli, the mevalonate pathway provides for production of isopentenyl pyrophosphate (IPP), which can be isomerized and polymerized into isoprenoids and terpenes of commercial value. Further, it has been shown that the expression of mevalonate-producing enzymes can inhibit cell growth and limit the productivity of microbial cultures.
Extraction and purification methods usually provide a low yield of the desired isoprenoid, as biological materials typically contain only small quantities of these compounds. Unfortunately, the difficulty involved in obtaining relatively large amounts of isoprenoids has limited their practical use. The lack of readily available methods by which to obtain certain isoprenoids has slowed down the progression of drug candidates through clinical trials.
Thus, it would be of significant value to terpenoid biosynthesis via the mevalonate pathway to find ways of increasing the availability of prenyl phosphate.